1. Approach to Metastatic Hormone-Sensitive Prostate Cancer

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3. Faculty
Alan H. Bryce, MD Vice Chair, Division of Hematology & Medical Oncology
Chair, Genitourinary Disease Group
Mayo Clinic Arizona
Scottsdale, Arizona
Alan H. Bryce, MD, has no real or apparent conflicts of interest to report.

4. Background
Data from RCTs from have redefined SOC options for mHSPC
CHAARTED/ECOG 3805 (US), STAMPEDE (UK), GETUG 15 (France)
Results have varied with regards to OS
Patient selection
Subsets
ECOG, Eastern Cooperative Oncology Group; mHSPC, metastatic hormone-sensitive prostate cancer; RCT, randomized controlled trial; SOC, standard of care.
Gravis G, et al. Lancet Oncol. 2013;14:
Sweeney CJ, et al. N Engl J Med. 2015;373:
James ND, et al. Lancet. 2016;387:

5. Dataset Study Accrual Years Treatment Arms N OS HR (95% CI) [months]
GETUG 15
ADT
ADT + D 75 mg/m2 max 9 cycles
385
1.01 ( )
[54.2 vs 58.9]
CHAARTED (E3805)
ADT + D 75 mg/m2 max 6 cycles
790
0.61 ( )
[44.0 vs 57.6]
STAMPEDE
ADT + D 75 mg/m2 max 6 cycles + Pred 10mg daily
ADT + D 75 mg/m2 max 6 cycles + ZA 4 mg + Pred 10 mg daily
1817*
0.76 ( )
[45 vs 60]
0.79 (0.66 v 0.96)
[45 vs 55]
ADT, androgen deprivation therapy; D, docetaxel; P, predisone; ZA, zoledronic acid.
*M1 disease only.
Gravis G, et al. Lancet Oncol. 2013;14:
Gravis G, et al. Eur Urol. 2015;[Epub ahead of print].
Sweeney CJ, et al. N Engl J Med. 2015;373:
James ND, et al. Lancet. 2016;387:

6. Lancet Oncology, Volume 14, Issue 2, Pages 149-158 (February 2013)
GETUG 15
Androgen-deprivation therapy alone or with docetaxel in non-castrate metastatic prostate cancer (GETUG-AFU 15): a randomised, open-label, phase 3 trial.
Dr Gwenaelle Gravis, MD, Prof Karim Fizazi, MD, Prof Florence Joly, MD, Prof Stéphane Oudard, MD, Franck Priou, MD, Benjamin Esterni, MSc, Igor Latorzeff, MD, Remy Delva, MD, Prof Ivan Krakowski, MD, Brigitte Laguerre, MD, Fréderic Rolland, MD, Christine Théodore, MD, Gael Deplanque, MD, Prof Jean Marc Ferrero, MD, Damien Pouessel, MD, Loïc Mourey, MD, Philippe Beuzeboc, MD, Sylvie Zanetta, MD, Muriel Habibian, Jean François Berdah, MD, Jerome Dauba, MD, Marjorie Baciuchka, MD, Christian Platini, MD, Prof Claude Linassier, MD, Jean Luc Labourey, MD, Prof Jean Pascal Machiels, MD, Claude El Kouri, MD, Prof Alain Ravaud, MD, Etienne Suc, MD, Jean Christophe Eymard, MD, Ali Hasbini, MD, Guilhem Bousquet, MD, Prof Michel Soulie, MD 
Lancet Oncology, Volume 14, Issue 2, Pages (February 2013)
DOI: /S (12)

7. GETUG 15: OS Crosses indicate censoring.
ADT, androgen deprivation therapy.
Crosses indicate censoring.
Gravis G, et al. Lancet Oncol. 2013;14:

8. GETUG 15: OS by Patient Subgroups
ADT, androgen deprivation therapy; ECOG, Eastern Cooperative Oncology Group; LLN, lower limit of normal; ULN, upper limit of normal.
*Abnormal: < LLN or > ULN
Gravis G, et al. Lancet Oncol. 2013;14:

9. Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer
CHAARTED (E3805)
Chemohormonal Therapy in Metastatic Hormone-Sensitive Prostate Cancer
Christopher J. Sweeney, M.B., B.S., Yu-Hui Chen, M.S., M.P.H., Michael Carducci, M.D., Glenn Liu, M.D., David F. Jarrard, M.D., Mario Eisenberger, M.D., Yu- Ning Wong, M.D., M.S.C.E., Noah Hahn, M.D., Manish Kohli, M.D., Matthew M. Cooney, M.D., Robert Dreicer, M.D., Nicholas J. Vogelzang, M.D., Joel Picus, M.D., Daniel Shevrin, M.D., Maha Hussain, M.B., Ch.B., Jorge A. Garcia, M.D., and Robert S. DiPaola, M.D.
The New England Journal of Medicine, Volume 373(8): ; August 20, 2015
DOI: /NEJMoa

10. CHAARTED: Overall OS
ADT, androgen deprivation therapy.
Sweeney CJ, et al. N Engl J Med. 2015;373:

11. CHAARTED: OS by Disease Volume
ADT, androgen deprivation therapy; NR not reached.
Sweeney CJ, et al. N Engl J Med. 2015;373:

12. CHAARTED: Overall PFS
ADT, androgen deprivation therapy; D, docetaxel.
Sweeney CJ, et al. N Engl J Med. 2015;373:

13. CHAARTED: OS by Subgroups
ADT, androgen deprivation therapy; ECOG, Eastern Cooperative Oncology Group.
Sweeney CJ, et al. N Engl J Med. 2015;373:

14. The Lancet, Volume 387, Issue 10024, 19-25 March 2016, Pages 1163-1177
STAMPEDE
Addition of docetaxel, zoledronic acid, or both to first-line long-term hormone therapy in prostate cancer (STAMPEDE): survival results from an adaptive, multiarm, multistage, platform randomised controlled trial
Nicholas D James, Matthew R Sydes, Noel W Clarke, Malcolm D Mason, David P Dearnaley, Melissa R Spears, Alastair W S Ritchie, Christopher C Parker, J Martin Russell, Gerhardt Attard, Johann de Bono, William Cross, Rob J Jones, George Thalmann, Claire Amos, David Matheson, Robin Millman, Mymoona Alzouebi, Sharon Beesley, Alison J Birtle, Susannah Brock, Richard Cathomas, Prabir Chakraborti, Simon Chowdhury, Audrey Cook, Tony Elliott, Joanna Gale, Stephanie Gibbs, John D Graham, John Hetherington, Robert Hughes, Robert Laing, Fiona McKinna, Duncan B McLaren, Joe M O’Sullivan, Omi Parikh, Clive Peedell, Andrew Protheroe, Angus J Robinson, Narayanan Srihari, Rajaguru Srinivasan, John Staff urth, Santhanam Sundar, Shaun Tolan, David Tsang, John Wagstaff , Mahesh K B Parmar, for the STAMPEDE investigators
The Lancet, Volume 387, Issue 10024, March 2016, Pages
doi: /S (15)

15. STAMPEDE: Overall Trial Design
ADT, androgen deprivation therapy; SOC, standard of care.
James ND, et al. Lancet. 2016;387:

16. STAMPEDE: OS for Pts with Metastatic Disease
SOC+Doc
SOC
Median OS (IQR)
SOC mos (23, 91), 350 deaths
SOC+Doc 60 mos (27, 103), 144 deaths
HR (95%CI): 0.76 (0.62, 0.92)
P value
Restricted mean survival time
SOC 61.4 mos
SOC+Doc 68.0 mos
Diff (95%CI) mos (3.6, 9.6 mos)
Doc, docetaxel; SOC, standard of care.
James ND, et al. Lancet. 2016;387:

17. STAMPEDE: OS in Overall Pt Population
SOC+ZA+Doc
SOC
SOC deaths
SOC+ZA+Doc deaths
HR (95%CI) 0.82 (0.69, 0.97)
P value
Doc, docetaxel; SOC, standard of care; ZA, zoledronic acid.
SOC alone - median OS 71m
SOC+ZA+Doc – median OS 76m
James ND, et al. Lancet. 2016;387:

18. ADT ± Docetaxel: OS for Low vs High Volume Disease
Study
Low Volume N
OS HR (95% CI)
[months]
High Volume
GETUG 15
ADT - 102
ADT/D - 100
1.02 ( )
[83.4 vs NR]
ADT - 91
ADT/D - 92
0.78 ( )
[35.1 vs 39.8]
CHAARTED (E3805)
ADT - 143
ADT/D - 134
0.6 ( )
[NR]
ADT - 250
ADT/D - 263
0.6 ( )
[32.2 vs 49.2]
ADT, androgen deprivation therapy; D, docetaxel; NR, not reached.
Gravis G, et al. Eur Urol. 2015;[Epub ahead of print].
Sweeney CJ, et al. N Engl J Med. 2015;373:

19. SWOG 9346
Hussain M, et al. J Clin Oncol. 2006;24:

20. Clinical Considerations for Docetaxel in mHSPC
Disease volume
Chemotherapy eligibility
Performance status
Comorbidities
Marrow reserve
Neuropathy
Prostate cancer independent life expectancy
Emphasis on QoL post chemotherapy
What is the patient’s rebound potential
mHSPC, metastatic hormone-sensitive prostate cancer; QoL, quality of life.

21. Key Patient Characteristics
Study
Median Age, yrs (range) PS
Newly Diagnosed
High Volume
Docetaxel post progression
GETUG 15 64
(57-70)
Median Karnofsky 100%
ADT 67%
ADT/D 75%
48%
ADT 62%
ADT/D 28%
CHAARTED (E3805) 63
(36-91)
ECOG %
73%
65%
ADT 60%
ADT/D 30%
STAMPEDE 65
(40-84)
WHO %
94% NA
ADT 41%
ADT/D 14%
Gravis G, et al. Eur Urol. 2015;[Epub ahead of print].
Sweeney CJ, et al. N Engl J Med. 2015;373:
James ND, et al. Lancet. 2016;387:

22. The Lancet Oncology, Volume 17, Issue 2, February 2016, Pages 243-256
STOpCaP
Addition of docetaxel or bisphosphonates to standard of care in men with localised or metastatic, hormone-sensitive prostate cancer: a systematic review and meta-analyses of aggregate data
Vale CL, Burdett S, Rydezewska LH, Albiges L, Clarke NW, Fisher D, Fizazi K, Gravis G, James ND, Mason MD, Parmar MKB, Sweeney CJ, Sydes MR, Tombal B, Tierney JF, for the STOpCaP steering group
The Lancet Oncology, Volume 17, Issue 2, February 2016, Pages
doi: /S (15)

23. STOpCaP: Meta-analysis of OS
SOC, standard of care.
Vale CL, et al. Lancet Oncol. 2016;17:

24. Evidence Synthesis
Docetaxel prolongs OS when added to ADT as first line therapy for mHSPC
But….
Generalizability of data to every patient is unclear
Impact on diverse disease phenotypes unclear
What constitutes low volume disease?
ADT, androgen deprivation therapy; mHSPC, metastatic hormone-sensitive prostate cancer.

25. Future Directions
First line therapy for mHSPC is now an active space for clinical studies
ADT + enzalutamide (NCT )
Docetaxel + rilimogene galvacirepvec [Prostvac] (NCT )
Ipilimumab + degarelix (NCT )
Apalutamide [ARN-509] (NCT )
Docetaxel + radium-223 (NCT )
ADT, androgen deprivation therapy; mHSPC, metastatic hormone-sensitive prostate cancer.

26. Summary
The value of docetaxel added to ADT for mHSPC is clearly established
…but patient selection for appropriateness of chemotherapy is imperative
Benefit of docetaxel is limited to high volume disease patients
Whether first-line docetaxel affects patient outcomes with subsequent therapies is unknown
Other established and experimental agents are being pursued in this disease setting
ADT, androgen deprivation therapy; mHSPC, metastatic hormone-sensitive prostate cancer.

27. Go Online for More CCO Coverage of Prostate Cancer!
Downloadable slidesets of key studies from ASCO 2016 selected by expert faculty Expert Analysis of key presentations from ASCO 2016
clinicaloptions.com/oncology